Stefano Guzzetti

Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog.

In 57 normal subjects (age 20–60 years), we analyzed the spontaneous beat-to-beat oscillation in R-R interval during control recumbent position, 90° upright tilt, controlled respiration (n = 16) and acute (n = 10) and chronic (n = 12) β-adrenergic receptor blockade. Automatic computer analysis provided the autoregressive power spectral density, as well as the number and relative power of the individual components. The power spectral density of R-R interval variability contained two major components in power, a high frequency at ∼0.25 Hz and a low frequency at ∼0.1 Hz, with a normalized low frequency: high frequency ratio of 3.6 ± 0.7. With tilt, the low-frequency component became largely predominant (90 ± 1%) withalow frequency: high frequency ratio of 21 ± 4. Acute β-adrenergic receptor blockade (0.2 mg/kg IV propranolol) increased variance at rest and markedly blunted the increase in low frequency and low frequency: high frequency ratio induced by tilt. Chronic β-adrenergic receptor blockade (0.6 mg/kg p.o. propranolol, t.i.d.), in addition, reduced low frequency and increased high frequency at rest, while limiting the low frequency: high frequency ratio increase produced by tilt. Controlled respiration produced at rest a marked increase in the high-frequency component, with a reduction of the low-frequency component and of the low frequency: high frequency ratio (0.7 ± 0.1); during tilt, the increase in the low frequency: high frequency ratio (8.3 ± 1.6) was significantly smaller. In seven additional subjects in whom direct high-fidelity arterial pressure was recorded, simultaneous R-R interval and arterial pressure variabilities were examined at rest and during tilt. Also, the power spectral density of arterial pressure variability contained two major components, with a relative low frequency: high frequency ratio at rest of 2.8 ± 0.7, which became 17 ± 5 with tilt. These power spectral density components were numerically similar to those observed in R-R variability. Thus, invasive and noninvasive studies provided similar results. More direct information on the role of cardiac sympathetic nerves on R-R and arterial pressure variabilities was derived from a group of experiments in conscious dogs before and after bilateral stellectomy. Under control conditions, high frequency was predominant and low frequency was very small or absent, owing to a predominant vagal tone. During a 9% decrease in arterial pressure obtained with IV nitroglycerin, there was a marked increase in low frequency, as a result of reflex sympathetic activation. Bilateral stellectomy prevented this low-frequency increase in R-R but not in arterial pressure autospectra, indicating that sympathetic nerves to the heart are instrumental in the genesis of low-frequency oscillations in R-R interval.

Continuous 24-hour assessment of the neural regulation of systemic arterial pressure and RR variabilities in ambulant subjects.

In this study, we tested the hypothesis that the neural control of circulation in humans undergoes continuous but in part predictable changes throughout the day and night. Dynamic 24-hour recordings were obtained in two groups of ambulant subjects. In 18 hospitalized patients free to move, direct high-fidelity arterial pressures and electrocardiograms were recorded, and in an additional 28 nonhospitalized subjects, only electrocardiograms were obtained. Spectral analysis of systolic arterial pressure and of RR interval variabilities provided quantitative markers of sympathetic and vagal control of the sinus node and of sympathetic modulation of vasomotor tone. With this approach, the low-frequency (approximately 0.1 Hz) component of RR interval and systolic arterial pressure variabilities is considered a marker primarily of sympathetic activity, whereas the high-frequency (approximately 0.25 Hz) component of RR interval variability, related to respiration, seems to be a marker primarily of vagal activity. We observed a pronounced and consistent reduction in the markers of sympathetic activity and an increase in those of vagal activity during the night. In the invasive studies, while the subjects were still lying in bed after waking up, the markers of sympathetic activity rose rapidly and concomitantly with a simultaneous vagal withdrawal. Noninvasive studies confirmed the early morning rise of the markers of sympathetic activity and the circadian pattern of sympathovagal balance. These data indicate that the ominously increased rate of cardiovascular events in the morning hours may reflect the sudden rise of sympathetic activity and the reduction of vagal tone.

Sympathetic predominance in essential hypertension: A study employing spectral analysis of heart rate variability

In this study on 91 subjects we tested the hypothesis of an enhanced sympathetic activity in uncomplicated essential hypertension employing spectral analysis of heart rate variability. With this technique the tonic sympathetic and vagal activities and their changes are respectively assessed by the power of approximately 0.1 Hz (low frequency, LF) and approximately 0.25 Hz (respiratory linked, high frequency, HF) components of the spectrum of the beat by beat variability of RR interval. When comparing the 40 subjects with diastolic blood pressure consistently greater than 95 mmHg (hypertensives, Ht), with 35 age-matched controls (diastolic arterial pressure less than 90 mmHg, Nt), we observed that LF was greater and HF smaller in Ht as compared to Nt, thus suggesting an enhanced sympathetic activity and a reduce vagal activity in Ht. Additionally, passive tilt, which in Nt enhances LF [delta = 26 +/- 2 normalized units (nu)] and reduces HF (delta = -22 +/- 2, nu), produced smaller (P less than 0.05) changes in Ht (delta LF = 6.3 +/- 2.7 and delta HF = -7.5 +/- 2.3 nu). Furthermore, the values of LF at rest and the altered effects of tilt on LF and HF were significantly correlated with the degree of the hypertensive state. Chronic beta-adrenergic blockade (atenolol 100 mg once daily for 2 weeks, n = 13) reduced heart rate and blood pressure (from 162/103 to 136/88 mmHg) together with a significant diminution of LF and an increase of HF. Thus, spectral analysis of RR variability appears to be a convenient non-invasive technique to follow the progressive alterations in sympatho-vagal balance present in essential hypertension.

Spectral analysis of heart rate variability in the assessment of autonomic diabetic neuropathy

We studied heart rate variability in 49 uncomplicated diabetics (27 with insulin therapy; 22 with oral hypoglycemic agents) and in 40 age-matched controls. An automatic autoregressive algorithm was used to compute the power spectral density (PSD) of beat by beat RR variability derived from the surface ECG. The PSD contains two major components (a low frequency approximately 0.1 Hz (LF) and a high frequency, respiratory linked, approximately 0.25 Hz (HF] that provide, respectively, quantitative markers of sympathetic and vagal modulatory activities and of their balance. As compared to controls, in diabetics, besides a reduced RR variance at rest (2722 +/- 300 and 1436 +/- 241 ms2, respectively), we observed during passive tilt an altered response of spectral indices of sympathetic activation and vagal withdrawal, suggestive of a complex modification in the neural control activities. In addition, we compared this approach to the commonly used clinical tests score, and observed that the latter provides overall results similar to those obtained with spectral changes induced by tilt (r = 0.42; P less than 0.01). Of potential clinical importance is that the data obtained with spectral analysis appear more thoroughly quantifiable and do not require the active collaboration of the patients.

Entropy, entropy rate, and pattern classification as tools to typify complexity in short heart period variability series

An integrated approach to the complexity analysis of short heart period variability series (/spl sim/300 cardiac beats) is proposed and applied to healthy subjects during the sympathetic activation induced by head-up tilt and during the driving action produced by controlled respiration (10, 15, and 20 breaths/min, CR10, CR15, and CR20 respectively). The approach relies on: 1) the calculation of Shannon entropy (SE) of the distribution of patterns lasting three beats; 2) the calculation of a regularity index based on an entropy rate (i.e., the conditional entropy); 3) the classification of frequent deterministic patterns (FDPs) lasting three beats. A redundancy reduction criterion is proposed to group FDPs in four categories according to the number and type or of heart period changes: a) no variation (0V); b) one variation (1V); and c) two like variations (2LV); 4) two unlike variations (2UV). The authors found that: 1) the SE decreased during tilt due to the increased percentage of missing patterns; 2) the regularity index increased during tilt and CR10 as patterns followed each other according to a more repetitive scheme; and 3) during CR10, SE and regularity index were not redundant as the regularity index significantly decreased while SE remained unchanged. Concerning pattern analysis the authors found that: a) at rest mainly three classes (0V, 1V, and 2LV) were detected; b) 0V patterns were more likely during tilt; c) 1V and 2LV patterns were more frequent during CR10; and d) 2UV patterns were more likely during CR20. The proposed approach based on quantification of complexity allows a full characterization of heart period dynamics and the identification of experimental conditions known to differently perturb cardiovascular regulation.

Symbolic Dynamics of Heart Rate Variability A Probe to Investigate Cardiac Autonomic Modulation

Background—Sympathetic and parasympathetic systems are considered the principal rapidly reacting systems that control heart rate. Methods and Results—We propose a symbolic analysis series to quantify the prevalence of sympathetic or parasympathetic cardiac modulation. This analysis decomposes the heart rate variability series in patterns lasting 3 beats and classifies them into 3 categories: nonvariable, variable, and very variable patterns referred to as 0V, 1V, and 2V patterns. First, we applied this method to experimental and pharmacological conditions characterized by sympathetic activation (tilt test, handgrip, nitroprusside, and high-dose atropine administration) or parasympathetic activation (phenylephrine and low-dose atropine administration) in 60 healthy subjects. An increase in sympathetic modulation and a vagal withdrawal elicited a significant increase in 0V patterns and a decrease in 2V patterns, whereas parasympathetic dominance induced the opposite, reflecting a reciprocal sympathovagal balance. The second part of the study considered a series of 300 beats before the onset of major arrhythmic events in patients with an implantable cardioverter-defibrillator. Symbolic analysis detected an increase in the percentage of 0V patterns before the onset of major arrhythmias compared with baseline (41.6±3.9% and 24.4±2.9%, respectively; P<0.01), indicating a sympathetic prevalence. On the other hand, the 2V patterns did not decrease before major arrhythmias, suggesting the presence of nonreciprocal autonomic modulations. Conclusions—Symbolic analysis of 3 beat sequences takes into account the different time course of sympathetic and parasympathetic cardiac modulations and seems appropriate for elucidating the neural pathophysiological mechanisms occurring during the short periods that precede acute cardiac events.

Information domain analysis of cardiovascular variability signals: evaluation of regularity, synchronisation and co-ordination.

A unifying general approach to measure regularity, synchronisation and co-ordination is proposed. This approach is based on conditional entropy and is specifically designed to deal with a small amount of data (a few hundred samples). Quantitative and reliable indexes of regularity, synchronisation and co-ordination (ranging from 0 to 1) are derived in a domain (i.e. the information domain) different from time and frequency domains. The method is applied to evaluate regularity, synchronisation and co-ordination among cardiovascular beat-to-beat variability signals during sympathetic activation induced by head-up tilt (T), during the perturbing action produced by controlled respiration at 10, 15 and 20 breaths/min (CR10, CR15 and CR20), and after peripheral muscarinic blockade provoked by the administration of low and high doses of atropine (LD and HD). It is found that: (1) regularity of the RR interval series is around 0.209; (2) this increases during T, CR10 and HD; (3) the systolic arterial pressure (SAP) series is more regular (0.406) and its regularity is not affected by the specified experimental conditions; (4) the muscle sympathetic (MS) series is a complex signal (0.093) and its regularity is not influenced by HD and LD; (5) the RR interval and SAP series are significantly, though weakly, synchronised (0.093) and their coupling increases during T, CR10 and CR15; (6) the RR interval and respiration are coupled (0.152) and their coupling increases during CR10; (7) SAP and respiration are significantly synchronised (0.108) and synchronisation increases during CR10; (8) MS and respiration are uncoupled and become coupled (0.119) after HD; (9) the RR interval, SAP and respiration are significantly co-ordinated (0.118) and co-ordination increases during CR10 and CR15; (10) during HD the co-ordination among SAP, MS and the respiratory signal is larger than that among the RR interval, SAP, MS and the respiratory signal, thus indicating that the RR interval contributes towards reducing co-ordination.

Circadian variation of spectral indices of heart rate variability after myocardial infarction

The circadian variations of spectral indices of heart rate variability were analyzed in 20 patients 4 weeks after a first and uncomplicated myocardial infarction (MI) and in 20 control subjects. R-R interval and variance showed a characteristic day-night pattern with a significant reduction of the latter parameter in patients after MI (10,967 +/- 1109 msec2 vs 16,860 +/- 2132 msec2). Control subjects were characterized by a predominance of low-frequency (approximately 0.1 Hz) component during the day and of high-frequency (approximately 0.25 Hz) component during the night, which reflected the expected 24-hour pattern of variation of sympatho-vagal balance. A 24-hour elevation (64 +/- 3 normalized units [nu] vs 56 +/- 2 nu; p less than 0.05) of the low-frequency component and a smaller (23 +/- 2 nu vs 32 +/- 2 nu; p less than 0.05) high-frequency component during the night differentiated patients after MI from subjects. The difference between the two groups was even more evident when the 24-hour sympatho-vagal balance was assessed with the low frequency/high frequency ratio. Thus spectral analysis of heart rate variability indicates that in patients after MI there is an alteration of neural control mechanisms as indicated by the presence of signs of sympathetic activation and by the attenuation of the nocturnal increase in vagal tone.

Altered pattern of circadian neural control of heart period in mild hypertension.

We addressed the problem of the circadian changes in neural control of heart period in ambulant hypertensive subjects. A running spectral analysis of R-R variability from Holter tapes provided markers of sympathetic, i.e. low-frequency component (LF) almost equal to 0.10 Hz, and vagal, i.e. high-frequency component (HF) almost equal to 0.25 Hz, controlling activities for the 24-h period of the recording. Significant circadian differences were observed in LF between the two groups of subjects: during night-time rest (0300-0400 h), LF was greater in hypertensives than in normotensives (56 +/- 2 and 48 +/- 2 nu, respectively; P less than 0.05). Furthermore, the difference between daytime and night-time LF values was progressively reduced with increasing severity of the hypertensive state, as assessed by resting arterial pressure levels. Spectral analysis of R-R variability suggests that essential hypertension may be characterized by a reduced day-night oscillation in sympathetic activity than can be quantified non-invasively using this approach.

Complexity and Nonlinearity in Short-Term Heart Period Variability: Comparison of Methods Based on Local Nonlinear Prediction

This paper evaluates the paradigm that proposes to quantify short-term complexity and detect nonlinear dynamics by exploiting local nonlinear prediction. Local nonlinear prediction methods are classified according to how they judge similarity among patterns of L samples (i.e., according to different definitions of the cells utilized to discretize the phase space) and examined in connection with different types of surrogate data: 1) phase-randomized or Fourier transform based, FT; 2) amplitude-adjusted FT, AAFT; 3) iteratively-refined AAFT, IAAFT, preserving distribution IAAFT-1; 4) IAAFT preserving power spectrum, IAAFT-2. The methods were applied on ad-hoc simulations and on a large database of short heart period variability series (~300 cardiac beats) recorded in healthy young subjects during experimental conditions inducing a sympathetic activation (head-up tilt, infusion of nitroprusside, or handgrip), a parasympathetic activation (low dose administration of atropine or infusion of phenylephrine), a complete parasympathetic blockade (high dose administration of atropine), or during controlled respiration at different breathing rates. As to complexity analysis we found that: 1) although complexity indexes derived from different methods were different in terms of absolute values, changes due to experimental conditions were consistently detected; 2) complexity was significantly decreased by all the experimental conditions provoking a sympathetic activation and by controlled respiration at slow breathing rates. As to detection of nonlinearities we found that: 1) IAAFT-1 and IAAFT-2 surrogates performed similarly in all protocols; 2) FT and IAAFT surrogates detected about the same percentage of nonlinear dynamics in all protocols; 3) AAFT surrogates were inappropriate with all the methods and should be dismissed in future applications; 4) methods based on overlapping cells with variable size were characterized by a larger rate of false detections of nonlinear dynamics; 5) short-term heart period variability at rest was mostly linear; 6) controlled respiration at slow breathing rates increased nonlinear components, while the separate activation of the two branches of the autonomic nervous system (i.e., sympathetic or parasympathetic) was ineffective at this regard